N-disubstituted carbamyl pyrazoles



United States Patent 3,303,130 N-DISUBSTITUTED QARBAMYL PYRAZOLES EuclidW. Bousquet, Wilmington, Del., assignor to E. I. du Pont de Nemours andCompany, Wilmington, Del., a corporation of Delaware No Drawing. FiledOct. 1, 1963, Scr. No. 312,871 6 Claims. (Cl. 260-294) This applicationis a continuation-in-part of my copending applications Serial No.190,212, filed April 26, 1962; Serial No. 158,102, filed December 8,1961; Serial No. 158,136, filed December 8, 1961, all three nowabandoned; the two latter applications each being continu ations-in-partof my application Serial No. 103,219, filed April 17, 1961 (nowabandoned) which in turn is a continuation-in-part of my applicationSerial No. 78,342, filed December 27, 1960 (now abandoned).

This invention relates to pyrazoles.

More specifically, this invention relates to nuclear nitrogensubstituted pyrazoles and to pharmaceutical compositions and processesutilizing as an essential active ingredient a novel pyrazole compoundwithin the scope of this invention.

The compounds of this invention have outstanding activity as analgesicagents, as measured in standard animal tests. Furthermore, certain ofthese compounds produce antiinflammatory activity similar to that shownby adrenocortical steroids, and some have antipyretic activity.

The above and other properties and utilities possessed by the compoundsof this invention will be elaborated .upon more fully hereinafter.

COMPOUNDS The new pyrazoles of this invention can be illustrated by thegeneral formula:

U\IRa where X is oxygen or sulfur;

R is methyl;

R is alkyl of 1 through 6 carbon atoms, alkenyl of 3 through 6 carbonatoms, alkoxyalkyl of 2 through 6 total carbon atoms, hydroxyalkyl of 2through 6 carbon atoms, methylalkylamino of 2 through carbon atoms,dialkylaminoalkyl where each of the alkyl groups in the dialkyl portionhas 1 or 2 carbon atoms and the remaining alkyl group has 1 through 4carbon atoms with a total of from 3 through 7 carbon atoms in thedialkylaminoalkyl group (CHA),,CN where a and A are as above; with thelimitation that R is joined to the carbamyl nitrogen by a primary orsecondary carbon atom; and where R and R can be joined-together andtogether with the carbamyl nitrogen form a heterocyclic structure fromthe following group:

morpholino, i.e.

L pyrrolidyl, i.e.

piperidyl, i.e.

dehydropiperidyl, i.e.

azabicyclononyl, i.e.

mono-substituted piperidyl of the structure where Y is H or CH Y is H,CH C H or COORg where R is alkyl of 1 through '4 carbon atoms;

Y is H,'hydroxy, alkyl of 1 through 9 carbon atoms,

cycloalkylalkyl of 4 through 9 carbon atoms, hydroxyalkyl of 2 through 9carbon atoms, alkoxyalkyl of 3 through 9 carbon atoms, trifiuoromethyl,COOR where R is alkyl of 1 through 4 carbon atoms,

Y and Y have the same meaning as above; R is hydrogen, alkyl of lthrough3 carbon atoms, trifiuoromethyl, fluorine, chlorine, bromine, sulfurpentafluoride or pyridyl; R is hydrogen, alkyl of 1 through 3 carbonatoms, trifiuoromethyl, sulfur pentafluoride, alkoxy of 1 through 3carbon atoms, amino, cyano, fluorine, chlorine, bromine or nitro; and Ris hydrogen, alkyl of 1 through 3 carbon atoms, trifiuoromethyl,fluorine, chlorine or bromine with the limitation that when X where issulfur or R is other than methyl R must be hydrogen; and with R R plus Rcontaining together a maximum total of 6 carbon atoms.

The compounds of this invention can exist as the isomeric formula:

R4- 5l-R X H 3 1NON L E/ In the instances where R and R are the same,these formulas are identical. However, where R and R are not the same,isomers are capable of existence. This is not surprising in view of theliterature on simple plyrazoles (see Elderfield, Heterocyclic Compounds,John Wiley, New York, 1957, vol. V, pages 91-92, showing that a mixtureof isomers may result from synthetic procedures). In the detaileddescription that follows in only some instances has the presence ofisomers been indicated, namely, as 3(5)-, 5 (3)-. The possibility ofsuch isomers exists in all instances where .the groups on the nuclearcarbons adjacent to the annular nitrogens are different. For simplicity,the compounds of this invention are generally named as the 3-isomerrather than as the S-isomer.

A preferred class of compounds are pyrazoles of the formula:

a where R is hydrogen or methyl; R is methyl, cyano, chlorine orbromine; and Y is the same as above.

Another preferred class of compounds are pyrazoles of the formula:

where R is hydrogen;

R is cyano, chlorine or bromine;

R is methyl; and

R is alkyl of 1 through 4 carbon atoms, alkenyl of 3 through 4 carbonatoms, or methylalkylamino where the alkyl is l or 2 carbon atoms, withthe limitation that R is joined to the carbamyl nitrogen by a primary orsecondary carbon.

Particularly preferred compounds from the above classes are thefollowing:

tem may be better adapted to certain classes, the disubstituted carbamylpyrazole system has been used for the major part for the naming ofexemplary compounds of the case.

COMPOUND UTILIZATION The new compounds of this invention are relativelystable. They are generally liquid, although some are relativelylow=melting solids. They have a wide range as liquids, generally of 200C. or more at atmospheric pressure. They can be used by themselves orwith other inert liquids, for hydraulic fluids. They are particularlyuseful as solvent for polar and non-polar compounds and can be used asthe reaction medium for such reactions as replacement of halogen inorganic compounds by the CN group of potassium cyanide.

Some of the new compounds of this invention have a bitter taste evenwhen diluted and are effective as denaturants, e.g., in alcohol.

The compounds of this invention have outstanding analgesic activity asmeasured in standard tests. Ac= tivity equal to or better than thatobtained with morphine has been obtained with a number of the compounds.The therapeutic ratios determined in these cases were also equal to orbetter than those found for morphine. Tests used to determine analgesicactivity were the Hot Plate test described by Eddy in the Journal ofPharmacology and Experimental Therapeutics, vol. 98, pages 121437 (1950)and a modification of the method of Bass and Brook described in theJournal of the American Pharma ceutical Association, vol. 41 (10), page569 (1952) in Which radiant heat is used to produce a response in testanimals. Both of these tests are standard tests used by investigators inthe field of analgesia and have been found to give indication ofpotential analgesic activity in man.

Of particular importance in the present invention are theantiinflammatory and antipyretic properties shown by certain of thesecompounds. The test used to determine the antiinfiammatory activity wasthe Cotton Pellet Granuloma test generally described by Meier, Schulerand De Saulles in Experiential, vol. 6, page 469 (1950). Results havebeen obtained which are comparable to those found with cortisone andbetter than those found with phenylbutazone, a clinically effectiveantiinfiarm matory agent. These findings suggest that these com poundsmay be useful in the treatment of inflammatory diseases such asrheumatoid arthritis, bursitis, and other diseases of connective tissueand in general in treatment of ailments in which cortisone is useful.Antipyretic activity as shown by certain compounds of this invention wasdetermined by standard laboratory tests.

In pharmaceutical application a compound of this invention will beadministered to the body orally, parenterally and by other methods. Thedosage will vary and will depend on such factors as the condition beingtreated; age and Weight of the recipient; the responsiveness of therecipient; prior, concurrent and intended subsequent medication andtreatment; general health of the recipient; frequency of treatment; andof course the purpose and nature of the effect desired.

Generally speaking, the active compound will be administered in aphysiologically beneficial amounts. Administration can be in a singledose or in a plurality of doses over an extended period of time. It willfurthermore be understood that every compound within this invention doesnot have an identical level of dosage requirement for therapeutic orprophylatic eltectiveness and therefore experts will understand thatsome dosage variation between compounds can be expected for maximumbenefits. It will, of course, also be understood that an initial dose,or first group of doses, in a course of treatment can be in greateramounts, if appropriate, for a particular medical situation and a rapidresponse is sought by the early administration of relatively large dosesand thereafter the minimally eltective dosage, or maintenance dosage, isdetermined.

A single dose will rarely exceed about 400 or 500 milligrams of activecompound within this invention, although larger amounts can be used ascalled 'for in any given situation. Extremely small doses will effectsome benefit but as a practical matter a single dose of less than about1 or 2 milligrams will seldom be used. For treating small animals withhigh physiological response and using highly active compounds, routineusage can be at much lower dosage levels however. Doses can be repeatedin the same or greater or lesser amounts over a period of time as longas improvement in the recipient is observed or as long as needed underthe circumstances.

The active compound will ordinarily be administered with a non-toxicpharmaceutical carrier in a variety of practical dosage forms. Thesedosage forms are novel compositions comprising the non-toxicpharmaceutical carrier and a physiologically beneficial amount of one ormore active compounds of this invention. These highly useful dosageforms constitute an important aspect of the present invention.

Suitable non-toxic pharmaceutical carriers or vehicles include liquidssuch as water, aromatic water, alcohols, syrups, elixirs, pharmaceuticalmucilages, such as acacia and tragacanth, oils such as of petroleum,animal, vegetable or synthetic origin, for example, peanut oil, soybeanoil, fish oil such as cod liver oil, or the like, for oraladministration; water, saline, aqueous lactose, aqueous maltose, aqueousglucose (dextrose), aqueous sucrose, or the like, for administration byinjection. Suitable solid carriers include soft gelatin capsules, hardgelatin capsules, slow or delayed release pills or capsules, powders,tableting vehicles, and the like. Suitable solid or liquid non-toxicpharmaceutical carriers are well known in the art and the selection ofcarrier can be from those appropriate and available in accordance withwell-known prescription techniques. The compositions of this inventiontherefore include such dosage forms as solution, suspensions, syrups,elixirs, tablets, capsules, powder packets and the like.

A vast number of suitable pharmaceutical carriers are described inRemingtons Practice of Pharmacy edited by E. W. Martin and E. F. Cook,12th edition, 1961, published by the Mack Publishing Company, Easton,Pennsylvania.

COMPOSITIONS In these novel compositions the active ingredient of theabove formulas will be present in a physiologically beneficial amount asmentioned above. In practice this means that the active ingredient willordinarily constitute at least about 0.0001% by weight based on thetotal weight of the composition. For oral adminstration in Water orother liquid medium, the concentration will ordinarily be in the rangefrom about 05 to 10.0% by weight of active ingredient. For injectionconcentrations from 2 to 20% are satisfactory. In tablets, powders,capsules and the like the amount of active ingredients may if desired beas much as 95 or 98% or more by weight of the total composition.

The active compounds of this invention can be formulated if desired withone or more pharmaceutically active materials for combination effects,treatments and benefits. Such materials include but are by no meanslimited to 6 vitamins, pain killers, tranquilizers, antibiotics,an-titussive agents, etc. The compositions can, of course, containsuitable pharmaceutical modifiers such as coloring agents, sweetening orother flavoring agents, solubilizing agents, etc. as will readily occurto persons skilled in this art.

PREPARATION OF. COMPOUNDS As mentioned above, the pyrazoles of the aboveformulas can be prepared by reaction of the appropriate pyrazolecontaining hydrogen on nuclear nitrogen with selected reactants as morefully described below.

Pyrazoles used in the processes as herein described are available bymethods of the chemical literature. Thus, a beta-diketone of thestructure R COCHR COR reacts with hydrazine to yield a pyrazole of theformula:

N R1 H where R R R R R and X have the same meaning as above.

In the preceding equation an illustrative carbamylating agent isdimethylcarbamyl chloride, although other available aliphaticN-disubstituted carbamyl halides, such as Where the halogen is bromine,can be employed.

A further method involves the preparation of a pyrazole having acarbonyl halide or thiocarbonyl halide on nuclear nitrogen. Suchcompounds are available by the reaction of a pyrazole having hydrogen onnuclear nitrogen and phosgene or thiophosgene as shown in the equation:

R4 H-Ra ml N X is... 11T

where R R R and X have the same meaning as above. The carbonyl chlorideor thiocarbonyl chloride thus available can be reacted with aliphaticsecondary amines (including cyclic amines) e.g. dimethylamine orpiperidine to give the desired new N-disubstituted carbamyl pyrazoles asfollows:

R2 where R R R R R and X have the same meaning as above.

The preceding reactions make no unusual requirements in the way ofcondiitons. In general, they are conducted at temperatures of 0-100 C.for times of the order of 172 hours. Pressure equipment may be necessarywhen the reaction is conducted above the boiling point of one of thereactants.

Particularly useful compounds and their preparation include thefollowing: 1-dimethylcarbamyl-3,5-dimethyl 4-nitropyrazole (see Example11) as well as similar nitro derivatives, is useful in the preparationof derivative compounds of this invention. Reduction of this compoundwith hydrogen in the presence of palladium-oncharcoal catalyst resultsin the preparation of l-dimethylcarbamyl- 4-amino-3,S-dimethylpyrazole.The latter compound is readily diazotized with nitrous acid in thepresence of hydrochloric acid in the cold to give the 4-diazoniumchloride of 1-dimethylcarbamyl-3,S-dimethylpyrazole. The diazonium groupcan be replaced by halogen under procedures known to the art to give forexample, the halogen derivatives of Examples 7 and 8. By the use of awatersoluble fluoride, the corresponding fiuoro derivative, i.e.,1-dimet-hylcarbamyl-3,5-dimethyl-4-tluoropyrazole, is obtained.

When 4-hydroxypyrazole is treated with dimethylc-arbamyl chloride by themethod previously described, there is obtained1-dimethylcarbamyl-4-hydroxypyrazole. Reaction of1-dimethylcarbamyl-4-hydroxypyrazole with diazomethane results in theformation of the ether, l-dimethylcarb-amyl-4-methoxypyrazole.

The diketone 2-methylhexane-3,5-dione on reaction with hydrazine hydrateand treatment of this product with dimethylcarbamyl chloride in thepresence of triethylamine in an inert solvent gives1-dimethylcarbarnyl-3- methyl-5-isopropylpyrazole.

The following examples illustrating the novel compounds of thisinvention, their preparation, their usefulness, and pharmaceuticalcompositions containing the novel compounds, are given in addition tothose given above to more clearly explain my invention.

Example 1.1-dim'ethylcarbamyl-3,5-dimethylpyrazole oH CH i oloomorrm iH3O H3O o ON(C Ha To a solution of 24 g. of 3,5-dimethylpyrazole in 1ml. of tetrahydrofuran was added 25 g. of triethylamine and then 27 g.of dimethylcarbamyl chloride. The reaction mixture was refluxed for onehour and then allowed to stand at room temperature for 15 hours. Theresidue, after removal of the solvent, was dried over sulfuric acid inan evacuated desiccator. This dry product Was then extracted withtetrahydrofuran. On distillation of this extract, a 21-g. fraction, B.P.7892 C./0.60.9 mm., was collected. Redistillation of this cut gave 14.5g. of N,N,3,5 tetramethyl-l-pyrazolecarboxamide (also named1-dimethyloarbamyl-3,S-dimethylpyrazole), B.P. 74.577.5 C./0.5 mm.; n1.5006. This compound is soluble in water, alcohol, and tetrahydrofuran.

Analysis-Calcd. for C l-1 N 02 C, 57.48; H, 7.78. Found: C, 57.34; H,8.40.

The compound can be "used as a solvent with excellent dissolving powerfor polar and non-polar compounds and is useful as a reaction medium fororganic reactions. It has analgesic and antipyretic activities.

The compound is formulated conveniently as an injectible solution of andby weight concentration in isotonic saline; as an injectible solution in5%, 10% and 15% by weight concentrations in aqueous sugars including inseparate solutions lactose, maltose, glucose (dextrose) and sucrose; inwater in 1%, 2%, 3% and 4% by weight concentration for oraladministration, with and without a flavoring agent, a coloring agent, anantitussive agent, etc.; and in 25, 50, and 100 milligram amounts instandard two-piece sealed hard gelatin capsules, as well as in softgelatin capsules, for oral administration. In pharmacologicalapplication it is administered in these dosage forms at dosage levels inthe range of 25 500 milligrams for treatment of physiological conditionsas described above.

Example 2.1-dimethylcarbamyl-3,4- (4,5) -diethyl-5(3 A solution of 43.3g. of 3,4(4,5)-diethyl-5(3)-methylpyrazole (obtained by the condensationof hydrazine with 3-ethylhexane-2,4-dione), 32 g. of triethylamine, and34 g. of dimethylcarbamyl chloride in 200 ml. of benzene was allowed tostand at room temperature for 65 hours. The solution was then pouredinto 200 ml. of water. The benzene layer was collected and washed withtwo ZOO-ml. portions of water. The benzene was removed by distillation.The triethylam-ine hydrochloride that crystallized in the residual oilwas removed by filtration and discarded. The filtrate was dissolved in300 ml. of ether and washed with four 150-ml. portions of water anddried over magnesium sulfate. The ether was removed by distillation andthe residual oil was distilled to give 37.4 g. of l-dimethylcarbamyl3,4-(4,5 -diethyl-5 (3 -methylpyrazole, B.P. 158-164" C. at 26 mm. Thecenter fraction had n 1.4940 and the following analysis:

Analysis.-Calcd. for C H N O: C, 63.2; H, 9.2; N, 20.1. Found: C, 64.3;H, 9.4; N, 20.1.

The compound of this example has analgesic activity. Formulated asdescribed for the compound of Example 1, the compound can be used as inthat example.

To a solution of 30.4 g. of 3,5-di-n-propylpyrazole (prepared from thereaction of hydrazine with nonane- 4,6-dione) in 250 ml. of ether wasadded 2.2 g. of dimethylcarbamyl chloride and 20 g. of triethylamine.The solution was allowed to stand at room temperature for 20 hours. Thetriethylamine hydrochloride that had precipitated was removed byfiltration and the filtrate was washed with ten -ml. portions of waterand dried over magnesium sulfate. The ether was removed by distillationand the oil that remained was distilled to give 16.2 g. of1-dimethylcarbamyl-3,5-dipropylpyrazole, B.P. 152- 154 C. at 16 mm. Theinfrared spectrum of this distillate indicated some unreacted pyrazolecontaminated the product. In another experiment the same reaction wasrepeated, using tetrahydrofuran as the solvent and the reaction wascarried out by heating the reaction mixture at reflux temperature for 17hours. Under these conditions, a 68% yield of1-dimethylcarbamyl-3,5-dipropylpyrazole, alternately namedN,N-dimethyl-3,5-di-npropylpyrazolecarboxamide, was obtained which aftertwo distillations boiled at 162-16? C. (20 mm.).

Analysis.-Calcd. for C H N O: C, 64.6; H, 9.48; N, 18.8. Found: C, 66.4;H, 9.73; N, 19.6.

This compound can be formulated in 10% by weight concentration inisotonic saline solution. The compound has analgesic activity.

Example 4.-1-dimethylcarbamylpyrazole doNtorrm A mixture of 34 g. ofpyrazole, 59 g. of dirnetbylcarbamyl chloride and 56 g. of triethylaminein 300 ml. of tetrahydrofuran was heated under reflux for 18 hours. Thecooled mixture was filtered to remove triethylamine hydrochloride andthe tetrahydrofuran was removed by distillation. The residual oil wasfreed of a small additional amount of triethylamine hydrochloride byfiltration and then dissolved in 250 ml. of ether. The ether solutionwas washed with two 100 ml. portions of water and dried over magnesiumsulfate. Distillation of the residue after removal of ether gave 25.8 g.of l-dimethylcarbamylpyrazole, alternately namedN,N-dimethylpyrazolecarboxamide, B.P. 102109 C. at 17 mm.Resdistillation gave 20.7 g. of material boiling at 107-112 C. at 18mm.; 11 1.5102.

Analysis.Calcd. for C H N O: N, 30.2. Found: N, 29.98. i

This compound has already been described and certain utilities discussedabove. It has a combination of analgesic and intiinflarnmatoryproperties. It can be administered suitably in capsules, by injection inaqueous medium or the like. The compound is also useful as a hydraulicfluid.

| comma A mixture of 83.2 g. of 3,5-diethylpyrazole (obtained byreaction of hydrazine with heptane-3,5-dione), 86 g. of dimethylcarbamylchloride, and 81 g. of triethylamine in 400 ml. of tetrahydrofuran washeated under reflux for 14 hours. The mixture was cooled and thetriethylamine hydrochloride was removed by filtration. The solvent wasremoved by distillation and the oil that remained was dissolved in 500ml. of petroleum ether and washed with ten 100-ml. portions of saturatedsodium chloride solution. Distillation gave117.5 g. ofl-dimethylcarbamyl-3,S-diethylpyrazo-le, also named.N,N-dimethyl-3,S-diethylpyrazolecarboxamide, B.P. 130-132 C. at 11 mm.;11 1.4943.

Analysis.Calcd. for C H N O: C, 61.6; H, 8.77; N, 21.5. Found: C, 62.0;H, 8.78; N, 21.54.

This compound can be formulated and used as described for the compoundin Example 1.

Example 6.1-dimethylcarbamyl-3,4,5-trimethylpyrazole I CON(CH )2 Amixture of 50 g. of trimethylpyrazole, 53.5 g. of dimethylcarbamylchloride, 50.5 g. of triethylamine, and 300 ml. of tetrahydrofuran washeated under reflux for 24 hours. The solid was removed by filtrationand washed with petroleum ether. The solvent was removed from thecombined filtrate and washings. The oil that remained was dissolved in500 ml. of petroleum ether and washed with eight 150-ml. portions ofsaturated sodium chloride solution and then dried over magnesiumsulfate. The drying agent and solvent were removed and the remaining oilwas distilled. The material that boiled at 129l31 C./ mm. was dissolvedin 400 ml. of petroleum ether and washed with five IOO-ml. portions ofsaturated sodium chloride solution. The solution was then dried overmagnesium sulfate and freed of solvent by distillation. Distillation ofthe remaining oil gave 55 g. of 1 dirnethylcarbamyl 3,4,5trimethylpyrazole, also named N,N-3,4,5-pentamethylpyrazolecarboxamide,B.P. 130 C./10 mm.; 11 1.5057.

Analysis.Calcd. for C H N O: C, 59.7; H, 8.34; N, 23.1. Found: C, 59.8;H, 8.55; N, 23.4.

Example 7.-1-dimethylcarbamyl-3,5-dimethyl- 4-br0m0pyraz0le Br HCH; rnolON(CHa)2 To 33.4 g. of l-dimethylcarbamyl-3,S-dimethylpyrazole, 30 g. ofsodium acetate, and 150 ml. of water was added 10 ml. (32 g.) of bromineover the course of five minutes. The solution was warmed at about 50 C.until the bromine color had faded and the solution was pale yellow.Crystals formed when the solution was cooled in ice. These werecollected and recrystallized from ethanol/ water mixture to give 44.2 g.of 1-dirnethylcarbamyl-3,5- dimethyl-4-bromopyrazole as colorlessneedles, M.P. 55.5-56.5 C. A sample of this compound which can also benamed N,N,3,5-tetramethyl-4-bromopyrazolecarboxamide was prepared foranalysis by crystallization from methanol/water M.P. 63.564.5 C.

Analysis.Calcd. for C H N BrO: C, 39.1; H, 4.92; Br, 32.5. Found: C,39.3; H, 4.91; Br, 32.5.

This compound has analgesic activity and is preferably administered byinjection in aqueous solution containing 1-10% by weight of this activecompound and 520% by weight of propylene glycol as a solubilizing agent.

Example 8 .-1 -dz'methy lcarbamyl-3 ,5 -dimethy l-4- chloropyrazole To acold solution of 33.4 g. of l-dimethylcarbamyl- 3,5-dimethylpyrazole and30 g. of sodium acetate in 200 ml. of water was passed in 15 g. ofchlorine over the course of five minutes. The solution became warm andturned orange. At the end of the addition of the chlorine, the color hadfaded and when the solution was cooled in ice,,crystals formed. Thecrude material was dissolved in petroleum ether and crystallized uponcooling to C. This once crystallized material was redissolved inpetroleum ether and passed over a bed of acid alumina which removedcolored material. When the eluate was concentrated and cooled in solidcarbon dioxide-acetone mixture, 20.3 g. of1-dimethylcarbamyl-3,5-dimethyl-4-chloropyrazole, alternately namedN,N,3,5-tetramethyl-4-chloropyrazolecarboxamide, M.P. 46-54 C., wasobtained. A sample was prepared for analysis by an additionalcrystallization at low temperature from petroleum ether. It melted at53-54 C.

Analysis.Calcd. for C H N ClO: C, 47.6; H, 6.01; Cl, 17.6. Found: C,47.5; H, 5.75; Cl, 18.1.

This compound has analgesic activity and can be administered as neededfor pain relief in an 8% injectible solution.

Example 9.1-dimetl1ylcarbamyl 3 trifluoromethyl-S- methylpyrazole "-01";

H OlN solvent) was added 125 ml. of tetrahydrofuran, 30.1 g. ofdimethylcarbamyl chloride, and 28.3 g. of triethylamine. The mixture wasrefluxed with stirring for 48 hours. The solid triethylaminehydrochloride precipitate was removed by filtration. The residual oil,after removal of the tetrahydrofuran, was diluted with ether and thiswas washed with four 50-ml. portions of saturated sodium chloridesolution. The ether solution was dried over sodium sulfate. Afterremoval of the ether and distillation there was obtained 43 g. (83%yield) of l-dimethylcarbamyl- 3-trifiuoromethyl-S-methylpyrazole, B.P.73-80 C./ 0.65 mm., of which a center fraction of 11 1.4320 wasanalyzed. This compound can also be named N,N,5(3)- trimethyl-3 (5-trifluoromethylpyrazolecarboxamide.

Analysis.-Calcd. for C H F N O: C, 43.44; H, 4.52. Found: C, 43.17; H,4.43.

The compound of this example has analgesic activity and is preferablyformulated using an injectible solution.

Example 10.1-dimethylcarbamyl-4-cyan0pyraz0le NC l N To 4.65 g. of4-cyanopyrazole (M.P. 91-92" C., obtainable from4-carb-oethoxypyrazole-see Jones, I. Am. Chem. Soc. 71, 3994 (1949)byreaction with ammonia to form the amide followed by dehydration) wasadded 2.24 g. of 53.5% sodium hydride in mineral oil, and 50 ml. oftetrahydrofuran. After hydrogen had evolved 5.38 g. of dimethylcarbamylchloride was added and allowed to stand for 16 hours. The mixture wasfiltered to remove sodium chloride and solvent removed by evaporation.After recrystallization of the solid residue from hexane, 6.52 g. ofwhite needle-like crystals, M.P. 7980.5 C. of1-dimethylcarbamyl-4-cyanopyrazole was obtained. The infrared spectrumwas in agreement with the assigned structure.

Analysis.Calcd. for C H N O: C, 51.21; H, 4.91; N, 34.13. Found: C,51.36; H, 5.05; N, 34.19.

This compound is a potent analgesic and has antiinflammatory activity.It can be formulated and used as in Example 1.

Example 11.1 dimethylcarbamyl-3,5-dimethyl-4-nitr0- pyrazole H-ondomom):

A mixture of 35.2 g. of 3,5-dimethyl-4-nitropyrazole, 27.8 g. ofdimethylcarbamyl chloride, 26.2 g. of triethylamine, and 300 ml. oftetrahydrofuran was heated under reflux for 20 hours. The triethylaminehydrochloride was removed by filtration and the filtrate was freed ofsolvent by distillation. The residue was dissolved in 250 ml. of etherand extracted with two 200-ml. portions of water and then two 200-ml.portions of saturated sodium chloride solution. After the solution wasdried over magnesium sulfate the solvent was removed. The residual oilwas distilled to give 27.7 g. ofl-dimethylcarbamyl-3,5-dimethyl-4-nitropyrazole, B.P. 138-144 C./ 0.5mm. This material solidified when allowed to stand. The solid wascrystallized from dichloroethylene-cyclohexane mixture to give 12.9 g.of impure starting material, M.P. 110-116" C. The liquors from thiscrystallization were evaporated to dryness and the solid that remainedwas crystallized from ether at 80 C. to give 10.4 g. of 1dimethylcarbamyl 3,5 dimethyl-4-nitropyrazole as needles, M.P. 77-77.9C. A mineral oil suspension had an infrared spectrum indicative of theassigned structure, having A 5.80, 5.87 for the compound, alternatelynamed N,N,3,5 tetramethyl-4-nitropyrazolecarboxamide.

12 Analysis.-Calcd. for C H N O C, 45.3; H, 5.71; N, 26.4. Found: C,46.4; H, 5.93; N, 26.4.

This compound has analgesic activity.

Example 12 .1-dimethycarbamyl-3,5-dimetl1yl-4- am in opyrazole CON(CH )2When 106 g. of 1-dimethylcarbamyl-3,5-dimethyl-4- nitropyrazolesuspended in ethanol was shaken with hydrogen in the presence ofpalladium-on-carbon catalyst at 20-35 C., three equivalents of hydrogenwere absorbed. The catalyst was removed by filtration and the ethanolwas removed by distillation on the steam bath. The residue wascrystallized from benzene/cyclohexane mixture to give 79.4 g. ofl-dimethylcarbamyl-3,5-dimethy-4-aminopyrazole, MP. -108.5 C., whichupon recrystallization had a melting point of 107 .9-108.9 C.

Analysis-Calcd. for C H N O: C, 52.8; H, 7.75; N, 30.8. Found: C, 53.0;H, 7.91; N, 30.8.

The analgesic activity of the 4-amino compound of this example is in thecodeine range. Suitable dosage forms using amounts described aboveinclude tablets, capsules, cough syrups also containing anti-tussiveagents and injectible solutions.

Example 13.1-N,N-dimethylcarbamyl-4-chl0r0pyraz0le A mixture of 104 g.of 1-N,N-dimet'hylcarbamylpyr.- zole, 136 g. of sodium acetatetrihydrate and 300 ml. of water was cooled in ice as 56 g. of chlorinewas passed into it over the course of an hour. The ice bath was removedand the mixture stirred for an additional half hour. The oil layer wasdissolved in 200 ml. of ether and the aqueous phase extracted with two200-ml. portions of ether. The combined ether solutions were washed with200 ml. of water then with two 200-ml. portions of saturated sodiumchloride solution. The ether was removed by distillation and the oilthat remained was distilled to give 83.3 g. of material boiling at128-139 C./22 mm. Fractionation of this distillate gives 51.9 g. of1-N,N-dimethylcarbamyl-4-chloropyrazole, B.P. 138- 142/ 22 mm. thatsolidifies to a crystalline material melting at 50.5-51.5".

Analysis.Calcd. for C H N ClO: C, 41.7; H, 4.66; N, 24.3. Found: C,41.7; H, 4.87; N, 24.0.

This compound has remarkable analgesic activity, approaching morphine inpotency. Its outstanding antiinflammatory activity resembles that ofcortison. Pharmaceutical compositions containing this compound can be inthe forms described in Example 1 and eleswhere above. Dosages arecomparable to cortisone for inflammatory conditions. Analgesicallyeffective dosages are in a range between those of morphine and those ofcodeine.

Example 14.1-N,N-dimethylcarbamyll-bromopyrazole To a mixture of 18.1 g.of 1-N,N-dimethylcarbamylpyrazole and 25.5 g. of potassium acetate in200 ml. of water was added 6.7 ml. of bromine over a period of onehalfhour at room temperature. After standing overnight, the aqueous solutionwas saturated with sodium chloride and extracted with four -ml. portionsof chloroform. The chloroform solution was dried and the solvent removedunder reduced pressure. The residue was fractionated to give 16.6 g. ofcrude product, B.P. 99108 C./2.7 mm. The crude product crystallized frompentane when the solvent was cooled to 10 C. There was obtained 8.73 g.(31% yield) of 1-N,N-dimethylcarbamyl-4-bromopyrazole, M.P. 4648 C.

The same compound was also obtained as follows: To a solution of 20.9 g.of 1-N,N-dimethylcarbamylpyrazole in 200 ml. of chloroform was added15.4 ml. of bromine in 25 ml. of chloroform. The solution was refiuxedfor 6 days, then treated with 5% sodium hydroxide and washed with icewater. The chloroform solution was dried and the solvent removed underreduced pressure. The residue was fractionated and the portion boilingat 104-108" C. at 1.5 mm. was crystallized from pentane to give 8.06 g.(25% yield) of l-N,N-dimethylcarbamyl-4- bromopyrazole, M.P. 45.5-47.5"C.

, Analysis.-Calcd. for C H BrN O: C, 33.0; H, 3.7; Br, 33.6; N, 19.3.Found: C, 33.19; H, 3.70; Br, 37.95; N, 20.0.

The infrared spectrum shows CH absorption at 3.19, 3.23 and 3.42 1. andcarbonyl absorption at 5.92/.t.

The same compound'is also obtained by reaction of 4-bromopyrazole withdimethylcarbamyl chloride.

This compound has potent analgesic and anti-inflammatory activity andfor these applications can be formulated and used as described above forthe compound of the preceding example A mixture of 85 g. of4-nitropyrazole, 85 g. of dimethylcarbamyl chloride, 81 g. oftriethylamine and 150 ml. of benzene was heated under reflux for 6hours. To the reaction mixture was added 1350 g. of warm benzene. Thebenzene solution was extracted with three 300-ml. portions of saturatedsodium chloride solutions and then reduced to a volume of 400 ml. bydistillation. When the solution cooled a solid crystallized which wascollected and washed free of a small quantity of colored material withcyclohexane to give 117.7 g. of 1-N,N-dimethylcarbamyl-4-nitropyrazole,M.P. 119.5-120.6. A second CH lur C1CON(CH3)2 crop of 12.8 (M.P.1185-1195") was obtained by conv centrating the liquors and dilutingthem with cyclohexane. Recrystallization from benzene gave an analyticalsample, M.P. 120.8-l2l.6.

Analysis.Calcd. for CsH N O C, 39.2; H, 4.38; N, 30.4. Found: C, 35.3;H, 4.31; N, 29.9.

This compound has high analgesic activity and is preferably administeredorally in tablet, syrup and capsule form. This compound is of coursealso useful as an intermediate in the preparation of related compounds.

Example 1 6.1-N,N-dimelhylcarbamyl-4-aminopyrazole OQNCCH H2 H2NC CH IIII II N HG N N O N o o monm Al mony,

with 200 ml. of benzene.

14 Analysis.Calcd. for C H N O C, 37.6; H, 3.42; N, 25.6. Found: C,38.0; H, 3.59; N, 26.0.

The 4-amino compound of this example has analgesic activity and ispreferably administered orally in tablet and capsule form.

Example 17.1,N,N-dimethylcarbamyl-4-methylpyrazole A mixture of 24.5 g.of 4-methylpyrazole (prepared by the method of Pine and Ercoli, Gazz.Chim. Ital., 81, 757 (1951)), 34 g. of dimethylcarbamyl chloride, 32 g.of triethylamine and 75 ml. of benzene was heated under reflux for 16hours. The cooled solution was diluted with 150 ml. of benzene. Thebenzene solution was washed with a mixture of ml. of water and 100 ml.of saturated sodium chloride solution and then with seven 100-ml.portions of saturated sodium chloride solution. The benzene solution wasdried over magnesium sulfate and distilled. The 1N,N-dimethylcarbamyl-4-rnethylpyrazole boils at -136/29 mm. and weighs30.7 g.; n,;, 1.5079.

The infrared shows absorption at 3.40, 5.90, 6.30, 7.23 u. The proton.n.m.r. spectrum shows a pattern consistent with the structure withbands at 1- of 2.09, 2.57, 6.91 and 8.03 of intensity relationship121:6:3.

Analysis.Calcd. for C H N O: C, 55.0; H, 7.26, N, 27.4. Found: C,55.2;-H, 7.56; N, 27.7.

The compound of this example has analgesic activity and can beadministered by injection in doses on the order of codeine. It can beformulated as described in Example 1.

Example 18.1-N,N-dimethylcarbamyl-3 (5) chl0r0-5-(3)-methylpyrazole Amixture of 57.8 g. of 5(3)-methyl-3(5)-chloropyrazole, 59 g. ofdimethylca'rbamyl chloride, 55.5 g. of triethylamine and 400 ml. ofbenzene was heated under reflux for 4 days. The triethylaminehydrochloride that had crystallized was removed by filtration and washedThe combined filtrate and benzene wash was extracted with ten 100-ml.portions of saturated sodium chloride solution. The benzene solution wasdistilled to give 69.2 g. of 1-N,N-dimethy1carbamyl- 3 (5 -methyl-5 (3-chloropyrazole, B.P. 74 0.1 mm., 71

Analysis.Calcd. for C H N C10; C, 45.0; H, 5.38; N, 22.4. Found: C,45.2; H, 5.52; N, 22.7.

This compound has analgesic activity. It can be formulated andadministered in like manner to the procedure described forl-dimethylcarbamyl-3,5-dimethyl-4-bromopyrazole in Example 7.

Example 19.1-N,N-dimethylcarbamyl-3 (5) A mixture of 22.0 g. of3-methylpyraz0le, 27.0 g. of triethylamine and 28.7 g. ofdimethylcarbamyl chloride The mixture was diluted with 200 ml. ofbenzene, and the filtrate was washed twice with ml. of saturated sodi-'mm. that contained amine hydrochloride.

Example 20.-1-dimethylcarbamyl-3,4-dimethylpyraz0le HzC-C-.CC H

ll 3 aC)zNCOCl H-O N A mixture of 48 g. of 3(5),4-dimethylpyrazole, 59g. of dimethylcarbamyl chloride, 56 g. of triethylamine, and 200 ml. ofbenzene was heated under reflux for hours. Enough water was added to thecooled mixture to dissolve the precipitated salt and the benzene layerwas diluted with 200 ml. of additional benzene. The benzene solution wasextracted with four 200-ml. portions of saturated sodium chloride.Distillation of the benzene solution gave material boiling at 133134/ 16The distillate was dissolved in 300 ml. of ether and washed with six100-ml. portions of saturated sodium chloride solution. The ethersolution was dried over magnesium sulfate and distilled to give 60.6 g.(73%) of l-d-imethylcarbamyl-3,4-dimethylpynazole, B.P. 132/16 mm. 111.5068.

Analysis.Calcd. for C H N O: C, 57.5; H, 7.85; N, 25.1. Found: C, 57.1;H, 8.14; N, 24.8.

This compound is a useful solvent for polar compounds. It also hasanalgesic activity that can be utilized in standard dosage forms.

Example 21.-1 -dimethy lcarbamy l-3-methy l-4-chl0r0pyrazole and 1-dimethy lcarbamy l-5-methyl-4-chl0r0pyrazole A mixture of 116 g. of3(5),4-chloropyrazole, 112 g. of dimethylcarbamyl chloride, 106 g. oftriethylamine and 500ml. of benzene was heated under reflux for 48hours. The salt that precipitated was dissolved in water and the benzenelayer washed with twelve 100-ml. portions of saturated sodium chloridesolution.

Example 22 .-1 -N-methyl-N-ethy lcarbamyl-4- chloropyrazole To a mixtureof 16.5 g. of 4-chloropyrazole-1-carbamyl chloride in 150 ml. ofanhydrous ether was added a mixture of 6.1 g. of methylethylamine and14.1 ml. of triethylamine in 25 ml. of ether at 510 C. over a period of0.5 hours. After stirring for 1 hour at 5 C., the mixture was thenrefluxed for 3 hours and allowed to stand at 2426 C. for 16 hours. Thesolid triethylamine hydrochloride was removed by filtration and washedwith .two 25-ml. portions of ether. The solvent was removed from thefiltrate by distillation and the residue distilled under reducedpressure. After a small forerun there was isolated 16.6 g. ofl-N-methyl-N- ethylcarbamyl-4-chloropyrazole, B.P. 7981 C. at 0.8 mm.(88% theory, 11 1.5149).

16 Analysis.Oalcd. for CqH10C1N3OZ C, 44.81; H, 5.37; Cl, 18.90; N,22.40. Found: C, 44.63; H, 5.41; Cl, 20.63; N, 22.48.

This compound has good analgesic activity.

Example 23.1-N,N-dimethylthiocarbamylpyrazole A mixture of 27.2 grams ofpyrazole, 59.5 grams of dimethylthiocarbamyl chloride, 48.5 grams oftriethylamine in 250 milliliters of dry tetrahydrofuran was refluxedthree hours with stirring. Triethylamine hydrochloride precipitated outabout 15 minutes after start of reflux. After standing at roomtemperature overnight, the solid triethylamine salt was filtered off andtetrahydrofuran was removed from the filtrate. The residual oil, dilutedwith ether, was then successively washed till substantially neutral withwater, dilute hydrochloric acid, and finally with more water. Afterdrying over anhydrous sodium sulfate, filtration and removal of ether,29 grams (50%) of a pale yellow, oily1-N,N-dimethylthiocarbamylpyrazole, B.P. 99-101" C./1.5 mm. (12 1.6055),was collected from distillation.

Analysis-Called. for C H N S: S, 20.64. Found: S, 20.76.

The compound of this example can be formulated as an injectible solutionof 5%, 10% and 15% by weight concentration in isotonic saline; as aninjectible solution in 5 10% and 15 by weight concentrations in aqueoussugars including in separate solutions lactose, maltose, glucose(dextrose) and sucrose; in water in 1%, 2%, 3% and 4% by weightconcentration for oral administration, with and without a flavoringagent, a coloring agent, an anti-tussive agent, etc; and in 25, 50, and100 milligram amounts in standard two-piece sealed hard gelatincapsules, as well as in soft gelatin capsules. Analgestic activity is inthe codeine range. The compound has antiinflammatory activity.

Example 24. 1-N,N-dimethyltlziocarbamyl- 4-br0m0pymz0le To 3.6 grams ofsodium hydride in 200 milliliters of methyl ether of ethylene glycol wasadded 22 grams of 4- bromopyrazole. After hydrogen had evolved, 18.5grams of dimethylth'iocarbarnyl chloride was added with slightexothermic reaction. The mixture was refluxed for 20 hours, then cooledand water added. The oily layer was extracted by diethyl ether andwashed with water. The ether solution was dried and ether evaporated. Ondistillation, there was obtained 20.5 grams of1-N,N-dimethylthiocarbamyl-4-bromopyrazole, Bl. 116-8 C., at 0.6 mm. Onstanding, the product solidified, M.P. 434 C.

Alternatively, the compound was prepared by reaction in tetrahydrofuranof bromopyrazole with dimethylthiocarbarnyl chloride in the presence oftriethylamine.

Arzalysis.Calcd. for C H BrN S: C, 30.77; H, 3.42. Found: C, 31.12; H,3.66.

The compound of this example has significant analgesic andantiinflammatory activity. It is conveniently formulated in 2% by weightconcentration in an aqueous vehicle.

1 7 Example 25 .-1 -N ,N -dimethy lthiocarbamyl 4-chloropyrazole Sodiumhydride (14 grams) in mineral oil was washed with benzene to remove themineral oil. To the sodium hydride was added 30.8 grams of4-chlolopyrazole: and then a benzene solution of 40 grams ofdimethylthiocarbamyl chloride. After the exothermic reaction subsidedthe mixture was refluxed for 40 hours, then cooled and washed withsodium carbonate solution and water. After drying over sodium sulfate,the solvent was removed by evaporation and the residual oil diluted withether, and a precipitate which formed was removed. The ether wasevaporated from the solution and the residue distilled to give 17 grams(30%) of 1-N,N-dimethylthiocarbarnyl- 4-chloropyrazole, boiling at 105-6C. at 0.7 mm.; n 1.6094, M.P. 46.7 (from petroleum ether B.P. 30- 60C.).

Analysis.-Calcd. for C H ClN S: C, 38.00; H, 4.22; Cl, 18.73; S, 16.89.Found: C, 38.71; H, 4.48; CI, 18.66; S, 16.31.

This compound has analgesic and antiinflammatory activity and can beadministered as needed for pain relief in an 8% injectible solution.

Example 26.1-N,N-dimethylthiocarbamyl- 4-methylpyrazole A stirredmixture of 20.5 grams of 4-methylpyrazole,--

34 grams of dimethylthiocarbamyl chloride, 28 grams of triethylamine,and 150 milliliters of dry' tetrahydrofuran was refluxed for hours.triethylamine hydrochloride was removed by filtration from the cooledreaction mixture and the filtrate concentrated by evaporation to removemost of the tetrahydrofuran. The resulting oil was dissolved in etherand washed successively with water, dilute hydrochloric acid, water,aqueous sodium bicarbonate, and water. The ether solution was then driedover sodium sulfate, decolorized with decolorizing charcoal, filtered,and distilled. Av substantially colorless oil was obtained, B.P. 96-8C./0.5 mm., n 1.5965, which on standing solidified, M.P. 56-7" C., andwas identified as 1-N,N-dimethy1thiocarbamyl-4- methylpyrazole byanalysis, infrared, and n.m.r. spectra.

Analysis.-Calcd. for C7H11N3SI C, 49.70; H, 6.51; S, 18.99. Found: C,49.47; H, 6.55; S, 19.27.

This compound has analgesic activity. It can be formulated with suitabletableting adjuvtants usinga conventional tableting machine with theactive ingredient constituting about 45-55% by weight of the tablet.Other ingredients include gelatin, magnesium stearate and starch.

Examples 27-31 (27) 1-N,N-dimethylthiocarbamyl-4-fluoropyrazole (28)1-N,N-dimethylthiocarbamyl-4-cyanopyrazole (29)1-N,N-dimethylthiocarbamyl-4-methoxypyrazole (30)1-N,N-dimethylthiocarbamyl-4-ethoxypyrazole 1 8. (3 11-N,N-dimethylthiocarbamyl-4-trifluoromethylpyrazole Example 32 Usingthe procedures of Example 23 and substituting appropriate reactants inequivalent amounts, 3(5)-methylpyrazole (obtained by condensation ofhydrazine with 3-ethylhexane-2,4-dione) is reacted withdimethylthiocarbamyl chloride in the presence of triethylamine to obtain1 N,N-dimethylthiocarbamyl-3(5)-methylpyrazole. This product can beformulated and used as in the preceding examples.

Examples 33-52 44 1-N,N-dimethylthiocarbamyl-3(5) ethyl-4- Thetheoretical amount of chloropyrazole (45 1-N,N-dimethylthiocarbamyl-3 5-ethyl-4- bromopyrazole (46) 1-N,N-dimethylthiocarbamyl-3 (5 -ethyl-4-fiuoropyrazole 47) 1-N,N-dimethylthiocarbamyl-3,4-diethylpyrazole (48)l-N,N-dimethylthiocarbamyl-3 (5 -ethyl-4- methoxypyrazole 49)1-N,N-dimethylthiocarbamyl-3 (5 -n-propyl-4- chloropyrazole .(50)1-N,N-dimethylthiocarbamyl-3 5 -n-propyl-4- bromopyrazole (511-N,N-dimethylthiocarbamyl-3 (5 -isopropyl-4- chloropyrazole 5 2)1-N,N-dime-thylthiocarbamyl-3 5 -isopropyl-4- methylpyrazole Example53.1-N;N-dimethylcarbamyl-3 (and 4 pentafluorothiopyrazole To a solutionof 11.8 g. (0.06 mole) of pentafluorosulfur pyrazole and 50 ml. oftetrahydrofuran was added at 05 C., 3.0 g. of NaH (53%)'in mineral oilsuspended in 10 ml. of tetrahydrofuran. The mixture was heated toreflux. During this time about 1.5 ml. of H was collected over water.Dimethylcarbamyl chloride (7.5 g.) was then added at room temperature.This mixture was stirredovernight, filtered and distilled through amolecular still. There was obtained 8.5 g. (56%) of carbamylatedpyrazole, B.P. 70 C. (pot. temp.)/0.24 The n.m..r. spectrum showed thiswas a mixture of 3-pentafluorothioand4-pentafluorothio-l-dimethylcarbamyl pyrazole.

and

Analysis.--Calcd. for C H F N OS: C, 27.17; H, 3.04; F, 35.82; N, 15.85;S, 12.09. Found: C, 27.99; H, 3.06; F, 34.81;N, 15.74; S, 12.05.

The pentafluorosulfur pyrazole was obtained by reacting diazomethanewith pentafiuorosulfur acetylene. The latter was prepared by brominationof chlorovinyl sulfur pentafluoride followed by treatment first with abase (KOH) and then with zinc.

The 1-N,N-dimethycarbamyl-3 (and 4)-pentafiuorosulfur pyrazole exhibitanalgesic properties.

Examples 5479 I 01 l (EMN Cl (I) Derivatives of 4 chloropyrazole 1carboxylic +Z N N aczd.-Der1vat1ves of 4-chlor0pyrazole-1-carboxy11cacid \I/ N/ were prepared by the following procedure. A solution of 0.1mole of the secondary amine, ZH, and 0.1 mole of triethylamine wasdissolved in 200 ml. of benzene, and ()1 Z 0.1 mole of4-chloropyrazole-l-carboxyl chloride was added in portions withstirring. Stirring was continued See the first column below for the11162111118 of overnight, and the precipitate of triethylaminehydrochloh following table ShOWS the am employed and ride was filteredoff. (In the case of high-boiling liquids, properties of the compoundsproduced:

Analysis Ex. Z M.P. B.P./mm. 11

C c H H caled. found caled. found (i311; 54 -NCHzCH CH 147-149/20 1.5083 47.4 48.1 5.0 5.2

(1H5 55 N-CH(CH3)1 142-143/17 1.5090 47.6 47.8 5.0 5.1

(IJH: CH: 55 -N0HOH,0H 127128.5l6 1.5052 50.1 50.6 5.5 5.7

57 NCH2CH(CH:)1 158-161/24 1.5033 50.1 50.1 6.5 6.4

(1H5 58 NCH2CH=CH 152-153.5/22 1.5241 48.1 48.1 5.1 5.5

(IJHa 59 NCH2CH1OCH3 152-154.5/10 1.5105 44.1 44.5 5.5 5.

(DI-Ia 60 NN(CH 1454455117 41.5 41.3 5.5 5.6

65- -OCH; 79.5-81 52.8 53.2 0.2 0.4

66..-.-- N CHzGHa 52.0-53.5 54.6 54.5 6.7 5.9

67- N GH CHZOHB 55.5-57 55.4 55.9 7.1 7.2

68.....- N CI-I CI-I CH CH 39-40 57.9 58.6 7.5 7.5

(3H5 69-.." OUH 49. 5-52 56.4 56.0 7.1 7.4

l CH3.

(244) l-dimethylcarbamyl-3 (5 -n-propyl-5 (3 -methyl- 4-methoxypyrazole(245 l-dimethyloarbamyl-3 (5 -isopropyl-5 (3 -methyl- 4-methoxypyrazole(246) 1-dimethylcarbamyl-3 (5 -ethyl-5 (3 -n-propyl- 4-methoxypyrazole(247) l-dimethylcarbamyl-3 5 -ethyl-5 (3 isopropyl- 4-methoxypyrazole(248 1-dimethylcarbamyl-3 (5 -trifluoromethylpyrazole (2491-dimethylcarbamyl-4-trifluoromethylpyrazole (250) 1-dimethylcarbamyl-3(5 -trifluoromethyl-4- aminopyrazole (25 1 l-dimethylcarbamyl-3 (5-methyl-5 3 -chloro- 4-trifluoromethylpyrazole (252)1-dimethylcarbamyl-4-n-propoxypyrazole (2531-dimethyloarbamyl-4-isopropoxypyrazole Examples 254-255 Using thegeneral procedures of Examples 54-79 the following compounds wereobtained:

(254)4-chloro-1-[N-methyl-N-(1-methyl-2-carboethoxyethyl)]carbamylpyrazole,B.P. l21-123/ 0.3 mm.; n 1.5023.

Analysis.Calcd. for C H N O Cl: C, 48.3; H, 5.9.

Found: C, 48.6; H, 6.0.

(255 4-chloro-1- [N-methyl-N-(Z-cyanoethyl) ]carbamylpyrazole, M.P. 7-72 Analysis.Calcd. for C H N OCl: C, 45.2; H, 4.3

Found: C, 45.2; H, 4.7.

Further compounds that can be prepared according to this generalprocedure are 4-chloro-1- [N-methyl-N-(methyl-2-N,N-dimethylcarbamylethyl) ]carbamylpyrazole,

4-chlorol [N-methyl-N- 1-methyl-4-carbethoxybutyl) carbamylpyrazole,

4-bromo- 1- [N-methyl-N- 1-ethyl-3 -cyanopropyl) 1- carbamylpyrazole,and

4-cyano-l-[N-methyl-N-( 1-methyl-4-N,N-diethylcarbamylbutyl) ]carbamylpyrazole.

The invention claimed is: 1. A compound of the formula where X isselected from the group consisting of oxygen and sulfur;

R is methyl;

R is selected from the group consisting of alkyl of 1 through 6 carbonatoms, alkenyl of 3 through 6 carbon atoms, alkoxyalkyl of 2 through 6total carbon atoms, hydroxyalkyl of 2 through 6 carbon atoms,methylalkylamino of 2 through carbon atoms, dialkylaminoalkyl where eachalkyl in the dialkyl portion has 1 through 2 carbon atoms and theremaining alkyl has 1 through 4 carbon atoms with a total of 3 through 7carbon atoms in said dialkylaminoalkyl,

where a is an integer of 1 through 5,

A is selected from the group consisting of H, CH and C H and wherein(CHA) has a total of 6 carbon atoms, and

R is selected from the group consisting of hydrogen and alkyl of 1through 4 carbon atoms,

where a and A are as above and R and R are separately selected from thegroup consisting of hydrogen and alkyl of 1 through 5 carbon atoms withthe limitation that R and R together cannot exceed 5 carbon atoms,(CHA),,CN where a and A are as above; with the limitation that R isjoined to the :carbamyl nitrogen by a primary or secondary carbon "atom;and where R and R together with the carbamyl nitrogen form a ringstructure selected from the group consisting of rnorpholino,pyrrolidino, dihydropiperidino, azabicyclononyl and piperidino of thestructure:,

where Y is selected from the group consisting of hydrogen and methyl;

Y is selected from the group consisting of hydrogen,

methyl, ethyl and COOR where R is alkyl of 1 through 4 carbon atoms; and

Y is selected from the group consisting of hydrogen, alkyl of 1 through9 carbon atoms, cycloalkylalkyl of 4 through 9 carbon atoms, hydroxy,hydroxyalkyl of 2 through 9 carbon atoms, alkoxyalkyl of 3 through 9carbon atoms, trifluoromethyl, COOR where R is alkyl of 1 through 4carbon atoms,

where R and R are each separately selected from the group consisting ofhydrogen and alkyl of 1 through 4 carbon atoms, dialkylaminoalky-l of 3through 8 carbon atoms where each alkyl in the dialkyl portion has 1through 2 carbon atoms and the remaining alkyl has 1 through 4 carbonatoms, pyrrolidinomethyl, benzyl, phenethyl, and 0-, mand p-tolylethyl,with the limitation that when Y, is CH Y and Y must be H;

R is selected from the group consisting of hydrogen and alkyl of 1through 3 carbon atoms, triflu-oromethyl, fluorine, chlorine, bromine,sulfur pentafluoride and py y R is selected from the group consisting ofhydrogen, chlorine, bromine, fluorine, alkyl of 1 through 3 carbonatoms, trifluoromethyl, sulfur pentafluoride, alkoxy of 1 through 3carbon atoms, amino, cyano and nitro; and

R is selected from the group consisting of hydrogen, alkyl of 1 through3 carbon atoms, trifluoromethyl, fluorine, chlorine, and bromine withthe limitation that when X is sulfur, R must be hydrogen and when R isother than methyl, R must be hydrogen; with the further limitation thatR R and R together have a maximum total of 6 carbon atoms.

2. 4-chloro-1-(4-isopropyl-l-piperidinocarbonyl)pyrazole.

3. 4 chloro 1-[4-(N,N-dimethylcarbamoyl)-l-piperidinocarbonyflpyrazole.

l4. 4 chloro-l-(4-hydroxy-l-piperidinocarbonyl)pyraz- 15. 4chloro-l-(N-mcthyl-N-isopropylcarbamoyl)pyraz- 6. 4chloro-1-(N-methyl-N-dimethylaminocarbamoyl) pyrazole.

(References on following page) 29 v 30 References Cited by the Examiner2,937,118 5/ 1960 Haxthausen et a1. 16765 UNITED STATES PATENTS3,041,344 6/1962 Ianssen 260-294 6/1933 Salzberg et aL 26o 243 5 3/ 963n n 0 9 3/ 1937 Sqlzberg et a1. 167-22 5 ALEX MAZEL, Primary Examiner.8/1947 H111 252149 1952 Hill 252 149 RIZZO, m 11/1955 Burness 260-310HENRY R. JILES, J. TOVAR, Assistant Examiners. 10/1958 Wagner et a1.167-65

1. A COMPOUND OF THE FORMULA